Abstract This proposal is designed to support a Research Specialist who is spearheading numerous initiatives using human induced pluripotent stem cells (hiPSCs) to study nervous system cancer biology. This specialist has extensive research experience with RASopathy cancer predisposition syndromes, beginning with her doctoral studies focused on generating Cardio-Facial-Cutaneous and Costello Syndrome preclinical zebrafish models, and over the past six years as a postdoctoral fellow and now Staff Scientist, developing translational research tools for Neurofibromatosis Type 1 (NF1). As such, the Research Specialist was responsible for the development of The Washington University NF Center iPSC Repository, the first and largest collection of NF1 patient-derived and CRISPR/Cas9-engineered hiPSCs. The Research Specialist?s expertise in generating and deploying NF1-hiPSCs has galvanized the development, funding and active participation in multiple projects within the Program Director?s laboratory, as well as multi-institutional programs involving collaborators modeling low-grade PNS tumors, malignant cancer progression, microglia contributions to nervous system tumor, and neuronal dysfunction in cancer. Moreover, the Research Specialist has pioneered the development of NF1 patient hiPSC lines to study the differential impact of patient-derived NF1 gene mutations on brain dysfunction, and specifically on nervous system RAS, cAMP and dopamine signaling, as well as to model nervous system cancer pathogenesis in genetically-engineered mouse models harboring NF1 patient Nf1 gene mutations. Collectively, the applicant has leveraged her considerable cross-species research experience to develop expertise in using hiPSCs to model human RAS-related cancer. As such, her hiPSC studies have revealed important new insights relevant to the pathogenesis of NF1-mutant nervous system tumors, which have helped to guide Dr. Gutmann?s laboratory studies in NF1 precision oncology. Finally, her commitment to the field, continued leadership in this area, and assistance in guiding iPSC-based projects, both at Washington University and at multiple academic institutions worldwide, are highly likely to provide clinically-actionable opportunities relevant to personalized risk assessment and medical management of people with RAS-related oncologic disease.